Fluoroalkylph enylcycloamidines and their production

ABSTRACT

Fluoroalkylphenylcycloamidines are useful for the control of ectoparasites in animals.

11' States Patent [1 1 Wollweher et al. I

[ Dec..3,l974

Wuppertal-Elberfeld, all of Germany [73] Assignee: BayerAktiengesellschaft,

Leverkusen, Germany [22] Filed: Feb. 22, 1971 [21] Appl. No.: 117,709

[30] Foreign Application Priority Data Feb. 26, 1970 Germany 2009019[52] US. Cl... 260/326.85, 260/239 B, 260/239 BE,

260/293.79, 424/244, 424/267, 424/274 [51] Int. Cl (307d 27/04 [58]Field of Search..... 260/239 B, 239 BE, 293.79,

[56] References Cited FOREIGN PATENTS OR APPLICATIONS 1,167,816 10/1969Great Britain ZED/326.85.

Primary Examiner-Joseph A. Narcavage 5 7] ABSTRACTFluoroalkylphenylcycloamidines are useful for the control ofectoparasites in animals.

14 Claims, N0 Drawings FLUOOMJMYLPH ENYLCYCLOAMIDINES AND THEIRPRODUCTION More particularly, the present invention is concerned withtluoroalkylphenylcycloamidines of the formula:

or a pharmaceutically acceptable non-toxic salt thereof,

wherein n is 3, 4 or 5,

m is O, l or 2,

R is trifluoromethyl or difluoromethyl,

R is halogen, such as fluorine, chlorine or bromine, alkyl of l to 4carbon atoms or alkenyl of 2 to 4 carbon atoms, and

R" is alkyl of l to 6 carbon atoms or alkenyl of 2 to 6 carbon atoms. I

These compounds are useful for the control and treatment of animalectoparasites particularly those of the class acarids.

Cyclic and acyclic phenylamidines are known. Up to now, only acyclicphenylamidines have been suggested as being effective against ticks. Oneof these compounds (I, South African Patent Specification 66/4135) waswithdrawn because of its instability. Of the known amidines, compound IIUS. Pat. No. 3,l89,648 is the closest compound to the chemical structureof the compounds of the present invention. However, said compound (ll)is not known to exhibit activity.

CH3 l I II ticularly against tick strains which have become resis tantto phosphoric acid. The compounds according to the invention are,moreover, stable when applied in the invention are produced by reactinganiline derivav v tives of the formula:

wherein R, R and m are as above defined, with lactams of the formula:

0 H w wherein R and n are as above defined, and

W is oxygen or sulphur or their salts or reactive derivatives,optionally in the presence of condensation agents.

By reactive derivatives are meant, for example, compounds of theformula:

wherein R" and n are as above defined, and Z is a reactive ester orether group. These derivatives are obtained by the reaction of lactamsor thiolactams of the formula:

II W wherein R", W and n are as above defined, with inorganic acids(such as hydrogen chloride, boron trifluoride, sulphuric acid) or withinorganic or organic acid chlorides (such as phosphorus oxychloride,phosphorus pentachloride, phosgene, thionyl chloride, benzoyl bromide ora mixture of phosgene/aluminium chloride or phosgene/hydrogen chlorideor phosgene/phosphorus oxychloride) or with trialkyl-oxoniumfluoroborates or with dialkylsulphates. The lactim esters are thenusually present as complex salts of the formula:

R-N 0111 .A ea

wherein R" and n are as above defined, and Q and A are for example thefollowing groups o-Poc|,. Poci, CI 'Cl CI, AICL. HCI, rocl,

OSOCl Cl -Continued o-co-c u s-co-c,H., Br. Cl O-CO-Cl. s-co-c| Clc,n,-s0,-o- Cl, Br O-alkyl BF, S-alkyl oso,-cu,, Br, 1. on

These reactions can be carried out in such a manner that, from thelactams and the acid halide, there is first prepared the reactive lactimester, optionally in the presence of solvents such as benzene, tolueneor tetramethylenesulphone; the substituted aniline is then wherein R"and n are as above defined, with substituted anilines in the presence ofdesulphurising agents, such as HgO, Ag O or Hg(CN) I It is also possibleto react acetals of the formula:

2) u R-N Alkyl 0 0 Alkyl wherein R" and n are as above defined, withsubstituted anilines.

Furthermore,-it is possible to acylate anilines of the formula:

wherein R, R and m are as above defined, with w-haloalkane acidchlorides, convert these with phosphorus halides into the imidechlorides of the formula:

and react thesewith amines of the formula:

' R." NH

wherein R is as above defined.

A further production route comprises heating arylisocyanates of the.formula:

wherein R, R and m are as above defined, with lactams of the formula:

R-N (0H,

wherein R and n are as above defined.

The CO evolution'which occurs is a good indication of the reactioncourse.

Instead of isocyanates, carbamic acid chlorides of the formula:

wherein R, R and m are as above defined, can also be used.

Finally, cyclic amidines of the formula:

wherein R, R, m and n are as above defined, can be reacted withalkylating agents of the formula:

B RII wherein R" is as above defined, and B is a reactive ester group,such as halogen, arylsulphonyloxy, e.g. benzenesulphonyloxy, tosyloxy oralkylsulphonyloxy, e.g. methanesulphonyloxy.

Illustrative aniline derivatives which can be used as starting materialinclude for example: 4-chloro-3- difluoromethylaniline, 4-bromo-3-difluoromethylaniline, 4-fluoro-3- difluoromethylaniline, 4-methyl-3-difluoromethylaniline, I 5-methyl-3- difluoromethylaniline,2-methyl-3-difluoromethylaniline, 6-methyl-3difluoromethylaniline, 6-chloro-3-difluoromethylaniline, 5-chloro-3- difluoromethylaniline,2-chloro-3- difluoromethylaniline, 4-ethyl-3=difluoromethylaniline,4-propyl-3-difluoromethylaniline, 4-butyl-3- difluoromethylaniline,4-allyl-3-difluoromethylaniline,

3-difluoromethylaniline, 4-chloro-3 trifluoromethylaniline, 4-bromo-3-trifluoromethylaniline, 4-fluoro-3- trifluoromethylaniline, 4-methyl-3trifluoromethylaniline, 5-methyl-3- trifluoromethylaniline, 2-methyl-3-trifluoromethylaniline, 6-methyl-3- trifluoromethylaniline, 6-chloro-3-trifluoromethylaniline, 5-chloro-3- trifluoromethylaniline, 2-chloro-3-trifluoromethylaniline 4-ethyl-3- trifluoromethylaniline, 4-propyl-3-trifluoromethylaniline, 4-butyl-3- trifluoromethylaniline,4-allyl-3-trifluoromethylaniline, 3-trifluoromethylaniline.

illustrative alkylating agents which can be used include those of theformula:

B RII for example butyl bromide, crotyl bromide, crotyl chloride, alkylbromide, allyl chloride, dipropyl sulphate, tosyloxypropane,tosyloxypentane, tosyloxyhexane.

When the compounds of the invention are in the form of their salts,preferred salts include the hydrochlorides, sulphates, phosphates,nitrates, acetates and phthalenedisulphonates.

The free bases and the salts exhibit strong acaricidal properties,particularly against acarids which as animal ectoparasites infestdomesticated animals such as cattle and sheep. They are therefore wellsuited for the control of animal ectoparasites of the class acarids. Aseconomically important ectoparasites of this nature which play a largepart especially in tropical and subtropical countries, there arementioned for example: the Australian and South American cattle tickBoophilus microplus, the South African cattle tick Boophilusdecoloratus, both from the family of lxodidae.

In the course of time, in various areas these ticks have becomeresistant to the phosphoric acid esters and carbamates used hitherto ascontrol agents, so that the success of control there is renderedquestionable. To safeguard an economic livestock husbandry in theinfestation areas, there exists therefore a need for agents with whichticks, even of resistant strains, for example of. the genus Boophilus,can be controlled with certainty. To a great extent resistant againstthe hitherto existing phosphoric acid ester agents and carbamates are,for example, in Australia the Ridgeland strain and the Biarra strain ofBoophilus microplus. The active compounds according to the invention areequally well effective both against the normally sensitive and theresistant strains, for example of Boophilus. For example, on the adultforms they have a strong inhibitory effect on the depositing of eggs.

The compounds of the present invention may be used monomethyl ether and'nonylphenol polyglycol ether. The emulsion concentrate so obtained isdiluted with water to the application concentration desired in each assuch or in the form of veterinary compositions which comprise thecompound in combination with a pharmaceutically acceptable (i.e.,physiologically compatible with the animal to be treated) nontoxic inertdiluent or carrier. Customary application methods include spraying,pouring, atomizing or application as a bath (dip). Any of the usualknown additives such as disinfect'ants can also be included in thecompositions of formulations. The techniques for producing suchcompositions and formulations are all per se well known.

EXAMPLE A In-vitro tests on ticks for inhibitory effect on eggdepositing I a r r 3 parts of active compound are mixed with 7 parts ofa mixture of equal parts by weight of ethyleneglycol case.

Adult, gorged female ticks of the species Boophilus microplus(resistant) are immersed for one minute in this preparation of activecompound. After immersion of, in each case, 10 female specimens of thevarious strains of ticks, the individual ticks are transferred intoplastics dishes, the bottom of which is covered with a filter paperdisc. After 35 days, the effectiveness of the preparation of activecompound is determined by ascertaining the inhibition of the depositingof fertile eggs compared with the egg deposition. of untreated controlticks. The effect is stated in percent, percent meaning that fertileeggs ceased to be deposited, and 0 percent meaning that the ticks havedeposited eggs in normal manner like the untreated control ticks.

The active compounds investigated, the concentrations tried, theparasites tested and the findings obtained can be seen from thefollowing Table:

TABLE 1 a In-vitro test for ovicidal effect on ticks Ovicidal effectagainst Boophilus microplus (Biarra strain) Inhibition with a concerntration of active compound in percent by Compounds tests weight of- Cl NCHN\ CH3 CH:

' I (known).

II (known) FzGH 0.03 0.02 01- -N CHQ FzCH 0. 05 0.02

The following non-limitative examples more particularly illustrate thepresent invention:

EXAMPLE 1 154 g (1.0 mole phosphorus oxychloride are added dropwise at20C to a solution of g (1.0 mole) 4- chloro-3-difluoromethylaniline and155.3 g (1.0 mole) N-butylpyrrolidone in 1,000 ml toluene, stirring iseffected for 90 minutes at room temperature followed by heating underreflux for 4 hours until the splitting off of HCl has ended. Aftercooling, the toluene solution is decanted off, the residue is taken upin water, rendered alkaline with solution of sodium hydroxide, and

the reaction product is extracted with a mixture of chloroform andether. After evaporation of the solvent and distillation under reducedpressure, 166 g l-butyl-2-(4-chloro-3-difluoromethylphenyl)-iminopyrrolidine of b.p. 154-l58/0.2mm Hg are obtained.

Compounds 2 through 32 set forth in Table 2 are produced in a manneranalogous to the procedure described above.

3. Same as above 3 CaH1 148150/0. 2

5. FzOH 3 CHzCH=CH-CH3 158/0. 3

6. FzHC 3 (EH; 149153/0. 2

C H2-C :C Hz C1 7. Same as above 3 CGHIQ 172-174/0. 2

8-- F 3 CaHo 150155/0.

9'. Same as above 3 OH2CH=CH2 138140/0. 1 -d0.. 3 H 144-148/0.1 11 .1103 CHzCH=CH-CH; 156158/0. 2

12 -d0 3 (EH: l52154/0. 2

C Hr-C :C H 2 13 d0 3 05H 162164/0. 2

16- (Ill 3 C4119 160-l64/0. 2

17 Same as above 3 CaHv 150l52/0. 2

.-d0 3 CHzCH=CHz 147 1!J'3"/0.03 19- F3? 4 CAHQ 162164/O. 2

20. Same as above 5 0 H} 172174/0. 2

mm. Hg

C Ha 127-130/ 1. 0

CHZ'C H=C Hz 10%112/0. 03

EXAMPLE 33 A solution of 9.9 g phosgene in ml toluene is added dropwiseto a solution of 16.5 g 4-chloro-3- difluoromethylaniline and 15.5 gN-butylpyrrolidone in 25 ml toluene, stirring is effected at 20 forminutes followed by heating under reflu-x for 4 hours. After the workingup described in Example 1, 13.2 g 1-butyl-2- (4-chloro-S-difluoromethylphenyl) -iminopyrrolidine of b.p. l54-158/0.2 mm Hg areobtained.

EXAMPLE 34 A solution of 31.4 g N-butylthiopyrrolidone and 40 g4-chloro-3-difluoromethylaniline in 40 ml ethanol is, with addition of75 g mercury oxide, stirred vigorously for 8 hours at 0 and then for 15hours at 80. Suction filtration from the precipitate is effected, theresidue is distilled in a vacuum, and 12.4 g l-butyl-2-(4-chloro-3-difluoromethylphenyl)-iminopyrrolidine of b.p. 154-158/0.2 mm Hg areobtained.

EXAMPLE 35 8.5 g (0.11 mole) allyl chloride are'added dropwise at 20 to24.5 g (0.1 mole) 4-chloro-3- difluoromethyliminopyrrolidine dissolvedin m1 tetrahydrofuran and heating under reflux is subsequently carriedout overnight. Suction filtration from the precipitate is effected. Thefiltrate is washed several times with water. After separation of theorganic phase, evaporation is effected and, after distillation at b.p.

' l30-160/0.2 mm Hg, a mixture of the formulae (11'Iz CH: CH:

from which, after column distillation, l-butyl-2-(4-chloro-3-difluoromethylphenyl)-iminopyrrolidine, b.p. l46-l47/0.05 mmHg, was able to be obtained pure. Yield 6.8 g.

EXAMPLE 36 EXAMPLE 37 50 ml butylcaprolactam and 25 ml 4-chloro-3-trifluoromethylisocyanate are heated under reflux until the CO evolutionhas ceased. The reaction product is distilled in a vacuum and 12.5 gl-butyl-2-(4-chloro-3- 30 trifluoromethylphenyl)-iminoazacycloheptane.l72-l 76/0.2 mm Hg, are obtained.

EXAMPLE 38- 31.4 g (0.2 mole) 'y-chlorobutyric acid chloride are addedto a solution of 37 g (0.2 mole) 4-chloro-3- trifluoroaniline in 350 mlbenzene,,heating under reflux is effected for 2 hours, followed bycooling, addition of 48.7 g phosphorus pentachloride, and gradualheating to reflux. After cessation of hydrogen chloride evolution, thephosphorus oxychloride formed is distilled off in a vacuum andl,4-dichloro-l-(4-chloro-3- trifluorophenylimino)-butane is obtained ashardly volatile oil. This is taken up in 100 ml benzene, added dropwiseat 20 to 33g (0.45 mole) butylamine in 200 ml benzene, and heated underreflux for 2 hours. Pouring into ice water is effected, followed byrendering alkaline with solution of sodium hydroxide and working upanalogously with Example I. 43 g l-butyl-2-(4- 50chloro-3-trifluoromethylphenyl)-iminopyrrolidine, b.p. l50-l55/0.05 mmHg, are obtained.

What is claimed is:

11. The compound which is 2. The compound of the formula:

Ar-N=[ Rik) R" is --C H and n is 3. F 3. The compound of the formula:

Ar-N=( J Bl l wherein Ar is R" is --C H and n is 3.

4. The compound of the formula:

' wherein nut:

wherein 6. The compound of the formula:

ArN=C (om wherein R" is C H and n is 3.

1 l i l2 7. The compound of the formula: wherein H W.. 7 Ar is I (CH FAr- 3 1* C1 RH wherein R" is C H and n is 4.

i i 1O 12. The compound of the formula:

A o1- m r is (CH2) n Ar- T R" is C H and n is 3. 8. The compound of theformula:

.. v d W R (Cl-1 7 1 wherein T Ar is ll wherein I wwcwwwww w c 2 5 A w If r is R 15 C.,H and n 15 5. 13. The compound of the formula: R" is --CH and n is 3.- 30

9. The compound of the formula:

L" wherein miar'am" Ar IS AYTS MY"P- v fii m 4 W c1 0 F H l C. R" is-C.,H and n is 3. 10'. The compound of the formula: is C and n is 4 9114. The compound of the formula:

I I 7. n I AP.

wherein i I l i v I l Ar is I v u- 01 wherein Ar is R" is C H and n is3. M lLThe compound of the formula: 'F H 2 n 7 C1 Az'-1\--C 5 v H R' is-C H and'n is 5.

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